The invention is in the field of non-steroidal compounds for estrogen-related treatments. Estrogenic and anti-estrogenic compounds have a generally recognised utility for estrogen-receptor related medical treatments, such as those for contraception and for treatment of menopausal complaints, osteoporosis, and estrogen dependent tumour control.
More precisely, the invention pertains to non-steroidal estrogen receptor modulating compounds with an 11H-benzo[b]fluorene, an 11H-indeno-[1,2-b]quinoline, a benz[a]anthracene or analogous skeleton. Analogous compounds with claimed usefulness in estrogen related medical treatments are described in U.S. Pat. No. 5,688,808 (1H-indeno[1,2-g]quinolines) and Morreal et al., J.Med.Chem., 1982, Vol 25, pp 323-326 (benz[a]anthracenes). Related estrogen receptor modulating compounds are described in EP 524, 742, EP 832 881 and U.S. Pat. No. 5,147,880 (1H-benzo[a]fluorenes].
Whereas further improvements for treatment of estrogen-related diseases remains desirable and there is a keen interest in compounds with affinity for the estrogen receptor, new compounds with an 11H-benzo[b]fluorene, an 11H-indeno-[1,2-b]quinoline, a benz[a]anthracene or analogous skeleton and affinity for the estrogen receptor cannot be learnt from these documents. The interest in new compounds with affinity for the estrogen receptor stems from unsatisfactory results with known estrogenic compounds for osteoporose treatment and treatment of other postmenopausal complaints and from the discovery of two distinct types of receptors, denoted ERxcex1 and ERxcex2 (see Mosselman et al., FEBS Letters 392 (1996) 49-53 as well as EP-A-0 798 378). Since these receptors have a different distribution in human tissue, the finding of compounds which possess a selective affinity for either of the two is an important technical progress, making it possible to provide an improved and/or more selective treatment in the field of estrogen-receptor related medical treatments, such as those for contraception and for treatment of menopausal complaints, osteoporosis, and estrogen dependent tumour control, with a lower burden of estrogen-related side-effects.
This invention provides new tetracyclic non-steroidal compounds having the formula I 
wherein,
one of Ra or Rb is ""Re;
Re and ""Re are OH, optionally independently etherified or esterified;
X is N or xe2x80x94(R1)xe2x80x94, wherein R1 is H, halogen, CN, optionally substituted aryl, (1C-4C)alkyl, (2C-4C)alkenyl, (2C-4C)alkynyl or (3C-6C)cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl groups can optionally be substituted with one or more halogens;
Y is N or xe2x80x94C(R2)xe2x80x94, with the proviso that X and Y are not both N, wherein R2 has the same meaning as defined for R1;
Z is xe2x80x94C(R3,""R3)xe2x80x94 or xe2x80x94C(R4,""R4)xe2x80x94C(R5,""R5)xe2x80x94, wherein R3, ""R3, R4, ""R4, R5, and ""R5, independently are H, (1C-4C)alkyl, (2C-4C)alkenyl or (3C-6C) cycloalkyl, which alkyl, alkenyl and cycloalkyl groups can optionally be substituted with one or more halogens.
The compounds of this invention have surprising and often selective interactions with estrogen receptors.
The reference to the meanings of R1 in the definition of R2 does not imply that R1 is the same as R2 in a compound as defined above. In fact, a more specific embodiment of this invention is a compound wherein at least one of R1 or R2 is halogen or fluorine substituted methyl.
Depending on the selection of a meaning of R3, ""R3, R4, ""R4, R5 and ""R5, compounds of the invention can have asymmetrically substituted atoms and can exist in enantiomeric pure forms or mixtures of enantimers differing from the usual 50/50 proportion.
Another specific embodiment of the invention is a compound according to formula I wherein X is xe2x80x94C(R1)13  and Y is N, having the formula II: 
wherein,
one of Ra or Rb is ""Re;
Re and ""Re are OH, optionally independently etherified or esterified;
Z is xe2x80x94C(R3,""R3)xe2x80x94 or xe2x80x94C(R4,""R4)xe2x80x94C(R5,""R5)xe2x80x94, wherein R3, ""R3, R4, ""R4, R5, and ""R5, independently are H, (1C-4C)alkyl, (2C-4C)alkenyl or (3C-6C) cycloalkyl, which alkyl, alkenyl and cycloalkyl groups can optionally be substituted with one or more halogens.
A preferred variant of this embodiment is Ra is ""Re and consequently Rb is H and further meanings are as defined for Formula II above. More preferred is R1 is halogen or fluorine substituted methyl.
Compounds according to formula II in which Z is xe2x80x94C(R3,""R3)xe2x80x94, Ra is ""Re and Rb is H have the formula III 
whereby the symbols have the meaning as defined for Formula II. Such compounds are named 11H-indeno[1,2-b]quinolines according to the convention of the chemical abstracts.
An embodiment of the invention is a compound according to Formula II, in which Z is xe2x80x94C(R4,""R4)xe2x80x94C(R5,""R5)xe2x80x94; Ra is ""Re; Rb, R4, ""R4, R5 and ""R5 are H, having the formula IV 
wherein,
R1 is H, halogen, CN, optionally substituted aryl, (1C-4C)allyl, (2C-4C)alkenyl, (2C-4C)alkynyl or (3C-6C)cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl groups can optionally be substituted with one or more halogens. Such compounds are named 3,9-dihydroxy-5,6-dihydro-benz[c]acridines. In this embodiment of the invention it is preferred that R1 is halogen or fluorine substituted methyl.
Another embodiment of the invention is a compound having Formula I, wherein X is N, Y is xe2x80x94C(R2)xe2x80x94, Ra is H and Rb is ""Re, having Formula V 
wherein,
Re and ""Re are OH, optionally independently etherified or esterified;
Z is xe2x80x94C(R3,""R3)xe2x80x94 or xe2x80x94C(R4,""R4)xe2x80x94C(R5,""R5)xe2x80x94, wherein R3, ""R3, R4, ""R4, R5, and ""R5, independently are H, (1C-4C)alkyl, (2C-4C)alkenyl or (3C-6C) cycloalkyl, which alkyl, alkenyl and cycloalkyl groups can optionally be substituted with one or more halogens;
R2 is H, halogen, CN, optionally substituted aryl, (1C-4C)alkyl, (2C-4C)alkenyl, (2C-4C)alkynyl, (3C-6C)cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl groups can optionally be substituted with one or more halogens.
In this embodiment it is preferred that R2 is halogen or fluorine substituted methyl and R3, ""R3, R4, ""R4, R5, and ""R5, independently are H or methyl. More preferred is that Z is xe2x80x94C(R4,""R4)xe2x80x94C(R5,""R5)xe2x80x94, wherein R4, ""R4, R5, and ""R5, are H.
Another embodiment of this invention is a compound according to formula I, wherein X is xe2x80x94C(R1)xe2x80x94, Y is xe2x80x94C(R2)xe2x80x94, having Formula VI 
wherein,
one of Ra or Rb is ""Re;
Re and ""Re are OH, optionally independently etherified or esterified;
R1 and R2 independently are H, halogen, CN, optionally substituted aryl, (1C-4C)alkyl, (2C-4C)alkenyl, (2C-4C)alkynyl or (3C-6C)cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl groups can optionally be substituted with one or more halogens;
Z is xe2x80x94C(R3,xe2x80x94R3)xe2x80x94 or xe2x80x94C(R4,""R4)xe2x80x94C(R5,""R5)xe2x80x94, wherein R3, ""R3, R4, ""R4, R5, and ""R5, independently are H, (1C-4C)alkyl, (2C-4C)alkenyl or (3C-6C) cycloalkyl, which alkyl, alkenyl and cycloalkyl groups can optionally be substituted with one or more halogens. In this embodiment it is preferred that R1 or R2 is halogen or fluorine substituted methyl.
Also preferred in this embodiment are those compounds according to Formula VI whereby Ra is ""Re; Rb is H; Z is xe2x80x94C(R4,""R4)xe2x80x94C(R5,""R5)xe2x80x94, wherein R4, ""R4, R5, and ""R5 are H, which compounds are having Formula VII 
wherein,
Re and ""Re are OH, optionally independently etherified or esterified;
R1 and R2 independently are H, halogen, CN, optionally substituted aryl, (1C-4C)alkyl, (2C-4C)alkenyl, (2C-4C)alkynyl or (3C-6C)cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl groups can optionally be substituted with one or more halogens, whereby it is preferred that R1 is halogen or methyl, optionally fluorine substituted, and R2 is hydrogen, which compounds are named 5,6-dihydro-3,9-dihydroxy-benz[a]anthracenes;
or compounds according to formula VI, whereby Z is xe2x80x94C(R3,""R3)xe2x80x94, having Formula VIII 
wherein,
one of Ra or Rb is ""Re;
R1 and R2 independently are H, halogen, CN, optionally substituted aryl, (1C-4C)alkyl, (2C-4C)alkenyl, (2C4C)alkynyl or (3C-6C)cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl groups can optionally be substituted with one or more halogens, whereby it is preferred that R1 is halogen or methyl, optionally substituted with fluorine, and R2 is hydrogen;
R3 and ""R3 independently are H or CH3, which compounds are named 11H-2-hydroxy-benzo[b]fluorenes.
In view of high selectivity for the ERxcex2, more preferred compounds are compounds according to formula VIII, wherein Ra is ""Re, Rb is H, R3, ""R3 are H or methyl, R1 or R2 is H and the other of R1 or R2 is halogen, CN, optionally substituted aryl, (1C-4C)alkyl, (2C-4C)alkenyl, (2C-4C)alkynyl or (3C-6C)cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl groups can optionally be substituted with one or more halogens, whereby it is preferred to select for R1 or R2 halogen or methyl, optionally substituted with fluorine. In general it is preferred that R3 and ""R3 are H.
The best mode of the invention, in view of selectivity for the ERxcex2, is a compound according to Formula IX 
wherein,
Re and ""Re are OH, optionally independently etherified or esterified;
Hal is fluorine, chlorine, bromine or fluorinated methyl, whereby from these possibilities for Hal the chlorine is most preferred.
The ester and ether compounds in the collection of compounds according to the invention often have activity as prodrug. Preferred ester and ether prodrugs are carboxylic acid esters or alkyl ethers on one or both hydroxyl groups, and more preferred prodrugs are (2C-6C)carboxylic acid esters, such as esters of (iso)butanoic acid, or (1C-4C) alkyl ethers. A prodrug is defined as being a compound which converts in the body of a recipient to a compound as defined by the formulas I to IX. Notably, the hydroxy groups as depicted in the formulas above can for example be substituted by alkyl*oxy, alkenyl*oxy, acyl*oxy, aroyloxy, alk*oxycarbonyloxy, sulfonyl groups or phosphate groups, whereby the carbon chain length of the groups denoted with an asterisk (*) is not considered to be sharply delimited, while aroyl generally will comprise a phenyl, pyridinyl or pyrimidyl, which groups can have substitutions customary in the art, such as alkyl*oxy, hydroxy, halogen, nitro, cyano, and (mono-, or dialkyl*-)amino. The length of the alkyl, alkenyl and acyl groups is selected depending on the desired properties of the prodrugs, whereby the longer chained prodrugs with for example lauryl or caproyl chains are more suitable for sustained release and depot preparations. It is known that such substituents spontaneously hydrolyse or are enzymatically hydrolysed to the free hydroxyl substituents on the skeleton of the compound. Such prodrugs will have biological activity comparable to the compounds to which they are converted in the body of the recipients. The active compound to which a prodrug is converted is called the parent compound. The onset of action and duration of action as well as the distribution in the body of a prodrug may differ from such properties of the parent compound.
Substitution variants of the compounds of the present invention are possible for similar use. A substitution variant is defined to be a compound which comprises in its molecular structure the structure as defined by the formula I. The skilled person inspecting the group of compounds provided by the present invention will immediately understand that modification by a substituent to the skeleton can yield a compound with similar biological activity as the compound without this particular substituent. It is common practise in the art to test such substitution variants for the expected biological activity so that it is a routine skill to obtain useful substitution variants of compounds according to the invention.
Other terms used in this description have the following meaning:
alkyl is a branched or unbranched alkyl group, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, hexyl, octyl, capryl, or lauryl;
alkenyl is a branched or unbranched alkenyl group, such as ethenyl, 2-butenyl, etc.;
alkynyl is a branched or unbranched alkynyl group, such as ethynyl and propynyl.
halogen refers to fluorine, chlorine, bromine and iodine;
aryl is a mono- or polycyclic, homo- or heterocyclic aromatic ring system, such as phenyl, naphtyl or pyridinyl; a monocyclic ring with 6 atoms is preferred for use;
aroyl is arylcarbonyl such as a benzoyl group;
alkanoyl means an oxo-substituted alkyl group, such as 2-oxobutyl or an acyl group;
acyl is an alkylcarbonyl group.
The prefixes (1C-4C), (2C-4C) etc. have the usual meaning to restrict the meaning of the indicated group to those with 1 to 4, 2 to 4 etc. carbon atoms.
The estrogen-receptor affinity profile of the compounds according to the present invention, makes them suitable as improved estrogens or anti-estrogens, in the sense that they can be used for estrogen-receptor related medical treatments, such as those for contraception or for treatment or prevention of benign prostate hypertrophy, cardiovascular disorders, menopausal complaints, osteoporosis, estrogen dependent tumour control or central nervous system disorders such as depression or Alzheimer""s disease.
In particular those compounds which have selective affinity for the ERxcex1 receptor are suitable for estrogen-receptor related medical treatments under diminished estrogen-related side-effects. This is most desirable when these compounds are used in the treatment of osteoporosis, cardiovascular disorders and central nervous system disorders such as depression or Alzheimer""s disease.
The compounds of the invention can be produced by various methods known in the art of organic chemistry in general. More specifically the routes of synthesis as illustrated in the schemes and examples can be used. A general description of the synthesis of halogenated benzo[b]fluorenes is depicted in scheme 1. 
The intermediate for further substitutions (strategic intermediate; e.g. compound 30 in examples 9, 10 and 11) can be made from its precursor in scheme 1 by adding methanesulphonic acid to the precursor and warming (about 60xc2x0 C.) for some time (about 30 minutes).
Ester prodrugs can be made by esterification of compounds with free hydroxyl groups by reaction with appropriate acyl chlorides in pyridine.
The present invention also relates to a pharmaceutical composition comprising the non-steroidal compound according to the invention mixed with a pharmaceutically acceptable auxiliary, such as described in the standard reference Gennaro et al., Remmington""s Pharmaceutical Sciences, (18th ed., Mack publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture.). The mixture of the compounds according to the invention and the pharmaceutically acceptable auxiliary may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. nasal spray. For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants. polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. The compounds of the invention may also be included in an implant, a vaginal ring, a patch, a gel, and any other preparation for sustained release.
Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof used in suitable amounts.
Furthermore, the invention relates to the use of the non-steroidal compound according to the invention for the manufacture of a medicament for estrogen-receptor related treatments and treatment of estrogen-receptor related disorders such as peri- and/or post-menopausal complaints. Thus the invention also pertains to the medical indications of peri- and/or post-menopausal (climacteric) complaints and osteoporosis, i.e. a method of treatment in the field of hormone replacement therapy (HRT), comprising the administration to a patient, being a woman, of a compound as described hereinbefore (in a suitable pharmaceutical dosage form).
Further, the invention relates to the use of the non-steroidal compound according to the invention in the manufacture of a medicament having contraceptive activity. Thus the invention also pertains to the medical indication of contraception, i.e. a method of contraception comprising the administration to a subject, being a woman or a female animal, of a progestogen and an estrogen as is customary in the field, wherein the estrogen is a compound as described hereinbefore (in a suitable pharmaceutical dosage form).
Finally the invention relates to the use of the non-steroidal compound for the manufacture of a medicament having selective estrogenic activity, such a medicament being generally suitable in the area of HRT (hormone replacement therapy).
The dosage amounts of the present compounds will be of the normal order for estrogenic compounds, e.g. of the order of 0.01 to 100 mg per administration.
The invention is further illustrated hereinafter with reference to some unlimitative examples and the corresponding formula schemes referred to.